Research

Original Investigation

Preexposure Prophylaxis for HIV Infection Integrated With

Municipal- and Community-Based Sexual Health Services
Albert Y. Liu, MD, MPH; Stephanie E. Cohen, MD, MPH; Eric Vittinghoff, PhD; Peter L. Anderson, PharmD;
Susanne Doblecki-Lewis, MD; Oliver Bacon, MD, MPH; Wairimu Chege, MD, MPH; Brian S. Postle, BS;
Tim Matheson, PhD; K. Rivet Amico, PhD; Teri Liegler, PhD; M. Keith Rawlings, MD; Nikole Trainor, MPH;
Robert Wilder Blue, MSW; Yannine Estrada, PhD; Megan E. Coleman, FNP; Gabriel Cardenas, MPH;
Daniel J. Feaster, PhD; Robert Grant, MD, MPH; Susan S. Philip, MD, MPH; Richard Elion, MD;
Susan Buchbinder, MD; Michael A. Kolber, PhD, MD

Invited Commentary page 85

IMPORTANCE Several randomized clinical trials have demonstrated the efficacy of Supplemental content at
preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) jamainternalmedicine.com
acquisition. Little is known about adherence to the regimen, sexual practices, and overall
effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections
(STIs) and community-based clinics serving men who have sex with men (MSM).

OBJECTIVE To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV
infection in a cohort of MSM and transgender women initiating PrEP in the United States.

DESIGN, SETTING, AND PARTICIPANTS Demonstration project conducted from October 1,

2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender
women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community
health center in Washington, DC. Data were analyzed from December 18, 2014, through
August 8, 2015.

INTERVENTIONS A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine

was provided free of charge for 48 weeks. All participants received HIV testing, brief
client-centered counseling, and clinical monitoring.

MAIN OUTCOMES AND MEASURES Concentrations of tenofovir diphosphate in dried blood

spot samples, self-reported numbers of anal sex partners and episodes of condomless
receptive anal sex, and incidence of STI and HIV acquisition.

RESULTS Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained
through 48 weeks. Based on the findings from the 294 participants who underwent
measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels
(consistent with ⱖ4 doses/wk) at follow-up visits. African American participants (56.8% of
visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to
have protective levels, whereas those with stable housing (86.8%; P = .02) and those
reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were
more likely to have protective levels. The mean number of anal sex partners declined during
follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal
sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100
person-years) but did not increase over time. Two individuals became HIV infected during
follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both
had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion.

CONCLUSIONS AND RELEVANCE The incidence of HIV acquisition was extremely low despite a
high incidence of STIs in a large US PrEP demonstration project. Adherence was higher Author Affiliations: Author
among those participants who reported more risk behaviors. Interventions that address racial affiliations are listed at the end of this
article.
and geographic disparities and housing instability may increase the impact of PrEP.
Corresponding Author: Albert Y. Liu,
MD, MPH, San Francisco Department
of Public Health, 25 Van Ness Ave,
JAMA Intern Med. 2016;176(1):75-84. doi:10.1001/jamainternmed.2015.4683 Ste 100, San Francisco, CA 94102-
Published online November 16, 2015. 6033 (albert.liu@sfdph.org).

(Reprinted) 75

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 Research Original Investigation Preexposure Prophylaxis for HIV Infection

I
n 2010, the Pre-exposure Prophylaxis Initiative (iPrEx) trial dispensed 1 month of tenofovir-emtricitabine. The sample size
of preexposure prophylaxis (PrEP) for human immunode- allowed us to estimate proportions within margins of sam-
ficiency virus (HIV) infection used a combination of daily pling error of 4.4% and to detect adjusted odds ratios of 1.7 to
oral tenofovir disoproxil fumarate and emtricitabine to dem- 2.3 depending on the predictor and outcome prevalence.
onstrate an overall 44% reduction in HIV acquisition among Participants returned for clinic visits at 4, 12, 24, 36, and
men who have sex with men (MSM) and transgender women 48 weeks for HIV and STI testing, clinical monitoring, and PrEP
receiving PrEP and greater than 90% efficacy among those with dispensing. Participants were encouraged to return 4 weeks
detectable drug levels in blood samples.1 After 2 additional ran- after stopping PrEP for a final evaluation and HIV test. Brief
domized clinical trials demonstrated safety and efficacy,2,3 this client-centered counseling was provided at all visits (eMethods
PrEP formulation was approved in the United States for the pre- 1 in the Supplement). Retention procedures were limited, with
vention of sexually acquired HIV infection in 2012.4 Two re- up to 3 contact attempts after a missed visit. Participants re-
cent studies of daily or intermittent PrEP among MSM5,6 ceived $25 for each scheduled visit. Preexposure prophylaxis
confirmed high PrEP efficacy. was discontinued in participants who underwent seroconver-
Men who have sex with men account for more than two- sion, who received counseling, partner services, and linkage
thirds of new HIV infections in the United States and are the to HIV primary care. The tenofovir-emtricitabine PrEP, test-
only risk group in whom infection rates are rising.7 Clinics that ing for HIV and STIs, and safety monitoring were provided free
treat sexually transmitted infections (STIs) and community- to participants. Among the 3 study sites, only the Washing-
based clinics serving MSM are promising clinical sites for PrEP ton, DC, site offered PrEP outside the Demo Project. The pro-
delivery,8 yet little is known about PrEP use in these settings. tocol was approved by the institutional review boards of the
Concerns have been raised regarding PrEP implementation, San Francisco City Clinic, Miami-Dade County Downtown STD
including risk compensation, 9,10 poor adherence, 11 drug Clinic, and Whitman-Walker Health.
resistance,12 and safety and toxic effects.13 We herein report
results of the Demo Project, a prospective, open-label dem- Measures
onstration project assessing PrEP adherence, sexual prac- PrEP Adherence and Engagement
tices, safety, and incidence of HIV and STI acquisition among Preexposure prophylaxis adherence was measured several ways.
MSM and transgender women in 3 US metropolitan areas At each visit, scores on a self-reported adherence rating scale15
heavily affected by HIV. were collected using an interviewer-administered question-
naire, pill counts were performed, and the medication posses-
sion ratio, defined as the number of dispensed pills divided by
the number of days between visits,16 was calculated. Dried blood
Methods spot (DBS) samples intended for measurement of tenofovir di-
Study Design and Participants phosphate (TFV-DP) concentrations (eMethods 2 in the Supple-
The Demo Project enrolled participants from municipal STI ment) were collected at all scheduled follow-up visits and at any
clinics in San Francisco and Miami and a community health visit where PrEP treatment was stopped. Concentrations of
center in Washington, DC, from October 1, 2012, through Janu- TFV-DP were measured in approximately 100 randomly se-
ary 23, 2014. The final follow-up occurred on February 10, 2015. lected participants per site; in addition, a decision was made af-
These clinics have access to large populations of at-risk MSM, ter completion of enrollment to perform TFV-DP DBS testing in
with annual HIV seroconversion rates of 2% or greater.14 Par- all African American and transgender participants, who were
ticipants were eligible if they were male at birth, were 18 years underrepresented in the overall sample.
or older, were fluent in English or Spanish, had a negative rapid Engagement with PrEP at each visit was assessed using a
HIV antibody test result at screening and enrollment and a 5-level ordinal measure in which the lowest level of engage-
negative fourth-generation antibody-antigen test result at ment was missing the visit, and increasing levels of engage-
screening, and had a creatinine clearance rate of at least 60 mL/ ment were identified for those attending the visit based on the
min (to convert to milliliters per second, multiply by 0.0167) following TFV-DP concentration levels: below the limits of
and a urine dipstick test with negative or trace findings of pro- quantitation and less than 2 (<350 fmol/punch), 2 to 3 (350-
tein. In addition, eligible participants reported any of the fol- 699 fmol/punch), or at least 4 (≥700 fmol/punch) doses/wk.
lowing in the preceding 12 months: condomless anal sex with This categorization of TFV-DP concentrations was used in the
at least 2 male or transgender female partners, at least 2 epi- iPrEx Open-Label Extension17 and derived from previous phar-
sodes of anal sex with at least 1 HIV-infected partner, or sex macokinetic modeling studies.18
with a male or transgender female partner and having a diag-
nosis of syphilis, rectal gonorrhea, or chlamydia. We ex- Sexual and Drug-Use Behaviors and Depression
cluded individuals with serious active medical conditions, a Sexual behaviors during the prior 3 months were assessed
history of pathologic fracture, or a positive finding for hepa- at screening and every 12 weeks using an interviewer-
titis B surface antigen or who used nephrotoxic medications. administered questionnaire, including the total number of anal
Race and ethnicity and sex assigned at birth and current gen- sex partners and number of episodes of insertive and recep-
der identity were self-reported and each assessed using a 2-part tive anal sex (RAS) with and without condoms. Participants were
question. We obtained written informed consent at screen- also asked about the use of alcohol, marijuana, amyl nitrite or
ing, and eligible individuals returned for enrollment and were butyl nitrite (poppers), cocaine, amphetamines, heroin, seda-

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 Preexposure Prophylaxis for HIV Infection Original Investigation Research

tives, methylenedioxy-methamphetamine (MDMA, or ec-

stasy), and drugs used to treat erectile dysfunction in the past Results
3 months. Polysubstance use was defined as using 3 or more of
the following: amyl nitrate or butyl nitrite, cocaine, amphet- Uptake for PrEP and baseline characteristics of the 557 partici-
amines, club drugs (ketamine, MDMA, or sodium oxybate), and pants in the Demo Project were described previously.25 Overall,
erectile dysfunction drugs.19 Depressive symptoms were as- 132 participants (23.7%) had an HIV-seropositive primary part-
sessed using the Patient Health Questionnaire-2.20 ner at baseline, including 122 participants (92.4%) who had a part-
ner receiving antiretroviral therapy and 107 (81.1%) who had a
HIV and STI Testing partner who was virally suppressed. However, 72 of 107 partici-
Testing for HIV acquisition was performed at all visits using pants (67.3%) with a primary partner with viral suppression re-
a rapid HIV antibody test (Clearview Stat-Pak/Complete; ported more than 1 anal sex partner in the past 3 months. At base-
Chembio Diagnostics Systems, Inc) and a fourth-generation line, any recreational drug use was reported by 413 participants
HIV antibody-antigen test (Architect; Abbott Diagnostics). In (74.1%); polysubstance use, by 112 participants (20.1%); amphet-
addition, participants at the San Francisco site underwent amine use, by 83 participants (14.9%); and injected drug use, by
acute HIV screening with pooled HIV RNA (10 samples/pool) 9 participants (1.6%). Testosterone or anabolic steroid use was
as standard practice in that clinic.21 In the Miami and Wash- rare (14 participants [2.5%]).
ington, DC, sites, an individual HIV RNA screen (APTIMA Among the 557 enrolled participants, 25 (4.5%) had no fol-
[GenProbe Diagnositics] or TaqMan, version 2.0 [COBAS]) low-up visits, whereas 383 (68.8%) completed all 5 visits. Re-
was performed at enrollment to screen for acute HIV infec- tention at week 48 included 437 participants (78.5%) overall and
tion. Those participants who demonstrated HIV seroconver- 232 (78.9%) among the 294 selected for TFV-DP testing; total
sion underwent HIV RNA viral load and resistance testing by follow-up was 481 person-years. Baseline correlates of reten-
genotyping and minor variant assays22 (eMethods 3 in the tion at week 48 are shown in Table 1. After adjusting for site, prior
Supplement). Urine specimens and rectal and pharyngeal PrEP knowledge and reporting of condomless RAS (ncRAS) at
swabs were tested quarterly for Neisseria gonorrhoeae and baseline were associated with being retained in the study.
Chlamydia trachomatis using a nucleic acid amplification
test (APTIMA Combo-2; GenProbe Diagnostics). Serologic PrEP Adherence and Engagement
testing for syphilis was performed quarterly with a VDRL or Mean PrEP adherence was 81.6% by pill counts and 85.9% by the
rapid plasma reagin test and confirmed with a fluorescent medication ratio, assessed in 533 participants. Self-rated adher-
treponemal antibody absorption test. ence was very good or excellent at 1959 of 2242 visits (87.4%).
Based on 1201 DBS samples provided by 294 participants who
Safety Monitoring attended follow-up visits, TFV-DP concentrations were in the
A clinical assessment for adverse events was performed at all protective range among an estimated 86%, 85%, 82%, 85%, and
follow-up visits (eMethods 4 in the Supplement). Serum cre- 80% of participants at weeks 4, 12, 24, 36, and 48, respectively.
atinine levels were measured at screening and quarterly, and In multivariable analyses, African American participants and
the creatinine clearance rate was estimated using the Cockroft- those from Miami were less likely to have protective TFV-DP lev-
Gault equation.23 els, whereas those who had stable housing and reported at least
2 condomless anal sex partners in the past 3 months were more
Statistical Analysis likely to have protective levels (Table 2). Trajectories of drug con-
Data were analyzed from December 18, 2014, through August centrations over time are shown graphically (eFigure in the
8, 2015. All statistical analyses were performed using STATA Supplement). Among 272 participants with at least 2 DBS
software (version 13.1; StataCorp). Logistic models were used samples tested, 170 (62.5%) had TFV-DP levels of at least 4 doses/
to assess baseline correlates of retention at 48 weeks. Our pri- wk at all visits tested and 8 (2.9%) had TFV-DP levels of less than
mary adherence outcome was having protective TFV-DP lev- 2 doses/wk at all visits tested.
els consistent with at least 4 doses/wk (eMethods 5 in the Preexposure prophylaxis engagement (including visit atten-
Supplement). We used a generalized estimating equation lo- dance and PrEP adherence) varied by site and by race or ethnic-
gistic model to evaluate baseline and time-dependent corre- ity (both, P < .001) (Figure 1). Furthermore, engagement at week
lates of having protective TFV-DP levels at each follow-up visit. 4 strongly correlated with engagement at week 48 (P < .001,
The factors associated with the outcome (P < .10) after adjust- Figure 2). Preexposure prophylaxis was interrupted 86 times
ment for site and visit were retained in the final model. For among 84 participants (15.1%) for reasons other than unavailabil-
analyses of adherence and PrEP engagement, participants with ity for or unwillingness to attend follow-up, HIV seroconversion,
TFV-DP results were weighted to be representative of all those or study completion, for a mean of 65 days that accounted for 24%
attending each visit. We assessed the association of PrEP en- of their follow-up; PrEP was restarted in 15 of those 84 partici-
gagement at week 4 with engagement at week 48 using a pro- pants (17.9%). Interruptions were mostly owing to participant
portional odds model.24 Trends in sexual behavior and drug preference, including adverse effects (25 times), concern about
use were evaluated using generalized estimating equation lo- long-term adverse effects (16 times), and low self-perceived risk
gistic and Poisson distribution models. Follow-up for the in- for HIV acquisition (21 times). Among participants who stopped
cidence of HIV and STI acquisition started at enrollment and PrEP owing to low perceived risk, 10 of 16 participants with avail-
ended at the last visit with an HIV or an STI test. able data (62.5%) reported ncRAS at that visit.

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 Research Original Investigation Preexposure Prophylaxis for HIV Infection

Table 1. Baseline Characteristics of Participants Retained Table 1. Baseline Characteristics of Participants Retained
Through the End of Study Through the End of Study (continued)

No. (%) of Participantsa P Value No. (%) of Participantsa P Value

Not Not
Retained Retained Retained Retained
b
Characteristic (n = 437) (n = 120) Unadjusted Adjustedc Characteristic b
(n = 437) (n = 120) Unadjusted Adjustedc
Site Consumption of ≥5
alcoholic drinks/d
San Francisco, 253 (84.3) 47 (15.7)
when drinking
California
in past 3 mo
Miami, Florida 98 (62.4) 59 (37.6) <.001 NA
No 390 (79.1) 103 (20.9)
Washington, DC 86 (86.0) 14 (14.0) .30 .59
Yes 47 (73.4) 17 (26.6)
Age, y
Any recreational
18-25 77 (68.8) 35 (31.3) drug use in past 3 mo
26-35 161 (77.0) 48 (23.0) No 111 (77.6) 32 (22.4)
.009 .12 .78 .56
36-45 115 (85.8) 19 (14.2) Yes 326 (78.7) 88 (21.3)
>45 84 (82.4) 18 (17.6) Amphetamine use
in past 3 mo
Race and/or ethnicity
No 366 (77.2) 108 (22.8)
White 226 (85.0) 40 (15.0) .09 .35
Yes 71 (85.5) 12 (14.5)
Latino 139 (72.4) 53 (27.6)
Polysubstance use
African American 25 (62.5) 15 (37.5) .002 .53 in past 3 mod
Asian 21 (80.8) 5 (19.2) No 343 (77.1) 102 (22.9)
.12 .36
Other 26 (81.3) 6 (18.8) Yes 94 (83.9) 18 (16.1)
Sex Injected drug use
in past 3 mo
Male 430 (78.5) 118 (21.5)
No 430 (78.5) 118 (21.5)
Transgender woman 5 (71.4) 2 (28.6) .65 .49 .96 .55
Yes 7 (77.8) 2 (22.2)
Other 2 (100) 0
Use of testosterone
Educational level or anabolic steroids
High school or less 55 (67.1) 27 (32.9) in past 3 mo
No 425 (78.3) 118 (21.7)
Some college 119 (78.8) 32 (21.2) .51 .48
.04 .41 Yes 12 (85.7) 2 (14.3)
College graduate 156 (79.6) 40 (20.4)
Any postgraduate 107 (83.6) 21 (16.4) Abbreviations: NA, not applicable; ncRAS, condomless receptive anal sex;
Income, $ PrEP, preexposure prophylaxis.
a
<20 000 128 (69.6) 56 (30.4) Data for race and/or ethnicity were missing for 1 participant; for income,
19 participants; and for health insurance, 1 participant.
20 000-59 999 158 (81.0) 37 (19.0) <.001 .07 b
Retained participants include those who completed their 48-week visit
≥60 000 139 (87.4) 20 (12.6) regardless of prior missed visits.
Health insurance c
Indicates adjusted for study site.
No 149 (71.6) 59 (28.4) d
Defined as use of 3 or more of the following substances in the past 3 months:
.002 .28
Yes 288 (82.8) 60 (17.2) amyl nitrite or butyl nitrite (poppers), club drugs (ketamine,
Living situation methylenedioxy-methamphetamine [ecstasy], or sodium oxybate), cocaine,
methamphetamine, or erectile dysfunction drugs.
Rent or own housing 362 (81.2) 84 (18.8)
Other (live with 75 (67.6) 36 (32.4)
friends or family, .002 .07 Sexual and Drug Use Behaviors and STIs
live in public housing, The mean number of anal sex partners in the past 3 months
or homeless)
Referral status
declined from baseline to week 48 (10.9 to 9.3; P = .04). Three
hundred sixty-five of 557 participants (65.5%) reported ncRAS
Self-referral 252 (84.6) 46 (15.4)
<.001 .08 at baseline, which remained stable during follow-up (P = .99)
Clinic referral 185 (71.4) 74 (28.6)
(Figure 3A). Overall numbers of RAS episodes in the past 3
Prior PrEP knowledge
months decreased (P = .007), driven by a decline in episodes
No 91 (64.1) 51 (35.9)
<.001 .01 with a condom (P < .001), whereas episodes without a con-
Yes 346 (83.4) 69 (16.6)
dom remained stable (P = .73). Site differences in sexual risk
ncRAS in past 3 mo
at baseline trajectories were observed, with increases in ncRAS (214 of 300
No 125 (68.3) 58 (31.7) [71.3%] to 187 of 247 [75.7%]) and mean number of ncRAS epi-
<.001 .002
Yes 312 (83.4) 62 (16.6) sodes (8.4 to 11) seen only in San Francisco (P < .05 for inter-
Postexposure action for both). Use of any recreational drugs (P = .42) and am-
prophylaxis use
at baseline visit phetamines (P = .41), heavy use of alcohol (≥5 drinks/d; P = .81),
No 422 (78.4) 116 (21.6) and use of amyl nitrite or butyl nitrite (P = .59) were stable,
.96 .63 whereas the use of powder cocaine (109 of 557 [19.6%] to 60
Yes 15 (78.9) 4 (21.1)
of 424 [14.2%]; P = .006) and club drugs (129 of 557 [23.2%]
(continued)
to 77 of 424 [18.2%]; P = .02) decreased.

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 Preexposure Prophylaxis for HIV Infection Original Investigation Research

Table 2. Correlates of TFV-DP Levels Consistent With Protection in Dried Blood Spot Samplesa
No. of Participants Level Indicative
Undergoing of ≥4 Doses/wk,
Characteristic Testingb % of Visitsc,d OR (95% CI)e P Value AOR (95% CI)f P Value
Site
San Francisco, California 103 89.6 1 [Reference] NA 1 [Reference] NA
Miami, Florida 95 65.1 0.21 (0.12-0.37) <.001 0.32 (0.17-0.60) <.001
Washington, DC 96 88.5 0.89 (0.47-1.70) .73 1.08 (0.54-2.19) .82
Age, y
18-25 62 77.5 1 [Reference] NA NA NA
26-35 109 85.4 1.41 (0.78-2.56) .25 NA NA
36-45 70 82.6 1.28 (0.64-2.55) .49 NA NA
>45 53 87.4 1.97 (0.91-4.28) .09 NA NA
Race/ethnicity
White 130 91.1 1 [Reference] NA 1 [Reference] NA
Latino 98 77.0 0.68 (0.35-1.30) .24 0.81 (0.41-1.61) .55
African American 33 56.8 0.22 (0.10-0.47) <.001 0.28 (0.12-0.64) .003
Asian 16 83.6 0.48 (0.13-1.80) .28 0.72 (0.17-3.03) .65
Other 17 82.4 0.43 (0.13-1.35) .15 0.42 (0.13-1.38) .15
Educational level
High school or less 37 71.7 1 [Reference] NA NA NA
Some college 79 79.9 1.08 (0.57-2.07) .81 NA NA
College graduate 178 87.7 1.76 (0.94-3.31) .08 NA NA
Income, $
<20 000 99 77.2 1 [Reference] NA NA NA
20 000-59 999 96 87.3 1.72 (0.97-3.06) .06 NA NA
≥60 000 88 87.0 1.12 (0.55-2.29) .75 NA NA
Health insurance
No 108 74.0 1 [Reference]
.04 NA NA
Yes 185 88.4 1.71 (1.03-2.85)
Living situation
Rent or own housing 68 86.8 2.32 (1.39-3.88) 2.02 (1.14-3.55)
Other (live with friends or family, 226 69.7 1 [Reference] .001 1 [Reference] .02
live in public housing, or homeless)
Referral status
Clinic referral 150 77.3 1 [Reference]
.07 NA NA
Self-referral 144 89.2 1.65 (0.97-2.83)
Prior PrEP knowledge
No 88 75.6 1 [Reference]
.95 NA NA
Yes 206 86.1 0.98 (0.57-1.68)
Depression
PHQ-2 score <2g 261 83.4 1 [Reference]
.89 NA NA
PHQ-2 score ≥2 33 85.0 0.96 (0.57-1.63)
ncRAS in past 3 mo
No 107 79.2 1 [Reference]
.37 NA NA
Yes 187 86.0 1.22 (0.79-1.89)
No. of ncRAS partners in past 3 mo
0-1 105 75.1 1 [Reference] 1 [Reference]
.003 .01
≥2 189 88.6 1.95 (1.26-3.01) 1.82 (1.14-2.89)
Consumption of ≥5 alcoholic drinks/d
when drinking in past 3 mo
No 265 83.9 1 [Reference]
.95 NA NA
Yes 29 81.4 1.02 (0.54-1.92)
Recreational drug use in past 3 mo
No 89 78.8 1 [Reference]
.26 NA NA
Yes 205 85.7 1.29 (0.83-2.00)
Amphetamine use in past 3 mo
No 253 82.8 1 [Reference]
.12 NA NA
Yes 41 90.6 1.88 (0.85-4.18)

Abbreviations: AOR, adjusted odds ratio; NA, not applicable; ncRAS, condomless doses/wk, weighted by site to reflect the full cohort and calculated as the
receptive anal sex; OR, odds ratio; PHQ-2, Patient Health Questionnaire-2; mean across weeks.
PrEP, preexposure prophylaxis; TFV-DP, tenofovir diphosphate. e
Odds ratios adjusted for site only.
a
Analysis includes all 294 participants who underwent measurement of TFV-DP f
Multivariable model included site, race or ethnicity, educational level, health
levels at a given visit. insurance, housing status, referral status, number of condomless anal sex
b
For time-dependent covariates, distribution of participants reflects the first partners, and erectile dysfunction drug use.
visit where TFV-DP levels were measured. g
Scores range from 0 to 6, with scores greater than 2 indicating a positive
c
Defined as protective level of TFV-DP. screen finding for depression.
d
Unadjusted prevalence of having TFV-DP levels consistent with at least 4

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 Research Original Investigation Preexposure Prophylaxis for HIV Infection

Figure 1. Distribution of Preexposure Prophylaxis Engagement by Visit Week

Level of engagement
No visit BLQ <2 Doses/wk 2-3 Doses/wk 4-7 Doses/wk
A Study site
100
Engagement, % of Participants

80

60

40

20

0
4 12 24 36 48 4 12 24 36 48 4 12 24 36 48
(n = 109) (n = 114) (n = 121) (n = 121) (n = 124) (n = 117) (n = 114) (n = 115) (n = 111) (n = 109) (n = 99) (n = 93) (n = 93) (n = 96) (n = 93)

San Francisco, California Miami, Florida Washington, DC

Visit Week by Study Site

B Race or ethnicity
100
Engagement, % of Participants

80

60

40

20

0
4 12 24 36 48 4 12 24 36 48 4 12 24 36 48 4 12 24 36 48
(n = 118) (n = 118) (n = 117) (n = 115) (n = 109) (n = 39) (n = 37) (n = 37) (n = 34) (n = 36) (n = 133) (n = 132) (n = 140) (n = 141) (n = 146) (n = 35) (n = 34) (n = 34) (n = 37) (n = 34)

Latino African American White Other

Visit Week by Race or Ethnicity

Engagement is a 5-level ordinal measure, with missing the visit as the lowest indicate number of participants contributing data at each time point.
level of engagement and increasing levels of engagement based on estimated Engagement varied by site and by race or ethnicity (P < .001). BLQ indicates
dosing frequency based on tenofovir diphosphate concentrations. Numbers below the limit of quantitation.

Overall, 147 participants (26.4%) had early syphilis, ing and enrollment and initiated PrEP. Two had a positive pooled
N gonorrhoeae, or C trachomatis at baseline, and 256 of 503 par- HIV RNA finding at enrollment, and infection was subsequently
ticipants who had at least 1 follow-up STI evaluation (50.9%) confirmed by results of individual quantitative RNA testing. The
were diagnosed as having at least 1 STI during follow-up. The third participant had a positive qualitative RNA test result at en-
proportion of participants who had early syphilis or infection rollment, which was confirmed by quantitative HIV RNA findings.
with N gonorrhoeae or C trachomatis at the urethra, rectum, One participant had a mixture of emtricitabine-resistant and wild-
or pharynx during each visit interval is shown in Figure 3B. type viruses (M184MI) 1 week after enrollment, which was not
Positive findings for rectal and pharyngeal STIs decreased from present at enrollment, suggesting acquired resistance; this par-
baseline to week 24, then increased (P < .05). The incidence ticipant switched to combination antiretroviral therapy (consist-
(95% CI) of STIs per 100 person-years was 48 (42-55) for ing of tenofovir-emtricitabine, darunavir ethanolate, ritonavir,
C trachomatis, 43 (37-49) for N gonorrhoeae, 12 (9-16) for syphi- and raltegravir potassium) and has maintained virologic suppres-
lis, and 90 (81-99) for any STI; in each case, the incidence was sion. Viral load was insufficient to perform resistance testing in
stable across quarterly intervals (all, P > .10). the second participant (120 copies/mL), and he has maintained
virologic suppression with antiretroviral therapy. The third par-
HIV Seroconversions and Incidence ticipant had no evidence of HIV resistance on results of standard
Three participants had acute HIV infection at enrollment. All three or ultrasensitive minor variant testing, although testing was per-
had negative rapid and antibody-antigen HIV test results at screen- formed 6 weeks after PrEP discontinuation.

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 Preexposure Prophylaxis for HIV Infection Original Investigation Research

Two participants acquired HIV infection during follow-

Figure 2. Preexposure Prophylaxis Engagement at Week 48
up, yielding an HIV incidence of 0.43 infections per 100 person- by Engagement at Week 4
years (95% CI, 0.05-1.54). The first infection was detected ap-
proximately 19 weeks after enrollment. This participant Level of engagement
reported last taking PrEP 37 days before seroconversion and No visit BLQ <2 Doses/wk 2-3 Doses/wk 4-7 Doses/wk
had TFV-DP levels of less than 2 doses/wk at his seroconver- 100
sion and all prior visits. The second seroconversion was de-

Engagement at Week 48, % of Participants

tected approximately 4 weeks after the 48-week visit, when
80
study drug was no longer dispensed. This participant had
TFV-DP levels consistent with daily dosing only at week 4,
dropping to less than 2 doses/wk or below the limits of quan- 60

titation thereafter. Neither participant had evidence of teno-

fovir-emtricitabine resistance on standard or ultrasensitive mi- 40
nor variant genotyping assays.

20
Safety
Nineteen serious adverse events were reported, 8 of which were
0
psychiatric (suicidal ideation and/or attempt, bipolar disor- No Visit BLQ <2 Doses 2-3 Doses 4-7 Doses
der, or anxiety); none were assessed as related to the study (n = 38) (n = 7) (n = 15) (n = 27) (n = 238)
Engagement at Week 4
drug. Twenty-three elevations of creatinine levels occurred in
13 of 557 individuals (2.3%), including 22 grade 1 and 1 grade 2
Proportion of participants with no visit attendance or with tenofovir
events. Only 3 elevations among 3 participants were con- diphosphate (TFV-DP) concentrations in dried blood spot samples in different
firmed on repeated testing results, and all resolved within 2 adherence categories at week 48 are stratified by visit attendance and TFV-DP
to 20 weeks without stopping PrEP. The PrEP regimen was dis- concentrations at week 4. This analysis includes 325 participants, 287 of whom
underwent measurement of TFV-DP levels at week 4 and 38 of whom missed
continued in 3 participants owing to elevated creatinine lev- the week 4 visit. Engagement at week 4 strongly correlated with engagement at
els; however, these elevations were not confirmed, and therapy week 48 (P < .001). BLQ indicates below the limit of quantitation.
was restarted in all cases. Two participants had grade 1 eleva-
tions of creatinine levels continuing at the end of the study. by other demographic characteristics, depression, or sub-
In one participant, the elevation was attributed to underlying stance use. Racial differences in pharmacokinetics have not
mild renal disease and assessed as unrelated to the study treat- been fully evaluated, but small studies have not identified such
ment. In the other participant, the elevation was assessed as differences to date.34 Lower adherence to medication regi-
related, but the participant chose to continue PrEP with his pri- mens has been reported among African Americans, including
mary care clinician after study completion. Twelve bone frac- those w ith HIV infec tion, 3 5 - 3 8 diabetes mellitus, 3 9
tures were reported during the study. All but one (tooth frac- hypertension,40 and heart failure.41 Other factors, including
ture) were explained by trauma, and none were related to the mistrust of health care professionals,35 privacy concerns,42
study treatment. lower levels of health literacy,39 and unmet medical and so-
cial structural needs,43 may explain these disparities and war-
rant further exploration in future PrEP programs. African
American MSM have high rates of HIV acquisition in the United
Discussion States, highlighting the importance of customizing support for
Despite low adherence seen in some placebo-controlled PrEP PrEP uptake and adherence for this population. Addressing
trials,26,27 we observed high adherence among MSM taking structural barriers, including lack of insurance and access to
PrEP in this open-label demonstration project. The study drug supportive health care, will also be critical. Several studies are
was detected in nearly all participants who underwent test- under way that evaluate novel PrEP delivery and support ap-
ing, and more than three-quarters achieved levels associated proaches in African American MSM, including a care coordi-
with high levels of protection.17,18 This higher adherence rate nation model in the ongoing HIV Prevention Trials Network
may be attributable to provision of open-label PrEP in a set- 073 demonstration study (http://www.hptn.org/research
ting of known efficacy 28,29 and to growing community _studies/hptn073.asp) and a mobile health adherence inter-
acceptance.8 Greater adherence was observed among those re- vention in Enhancing PrEP in Communities.44
porting greater sexual risk, a finding that was also seen in the The reasons for lower retention and adherence in the Mi-
Global iPrEx Study30 and the Partners PrEP Study31 and is ex- ami site are unclear. Although Miami participants were
pected to increase the impact and cost-effectiveness of younger, were more likely to be Latino, and had lower educa-
PrEP.32,33 Adherence to PrEP was not diminished among people tional levels,25 these variables were not independently pre-
using alcohol or other recreational drugs. dictive in adjusted analyses; likewise, although PrEP aware-
Despite the achievement of most participants of protec- ness was lower in Miami, it did not predict retention there.
tive PrEP levels, lower drug levels were observed among Afri- Unmeasured factors, including transportation, social sup-
can American participants, those with unstable housing, and port, health literacy, acculturation, and community accep-
those at the Miami site. These disparities were not explained tance of PrEP, may help to explain this disparity.

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 Research Original Investigation Preexposure Prophylaxis for HIV Infection

Figure 3. Sexual Behaviors and Sexually Transmitted Infections (STIs) in the Demo Project

A Receptive anal sex B Positive results of STI testing

Reported ncRAS Rectal STI Urethral STI
RAS episodes with a condom Pharyngeal Primary, secondary,
RAS episodes without a condom STI or early latent syphilis
70 12 18

STI Positivity Rate by Visit Week, % of Participants

60 14
10
Reported ncRAS, % of Participants

12

Mean No. of RAS Episodes

50
8
10
40
6 8
30
6 A, Participants reporting condomless
4
20 receptive anal sex (ncRAS) and mean
4 number of RAS episodes with and
10
2 without a condom. B, The positive STI
2
findings by anatomic site include
Neisseria gonorrhoeae and Chlamydia
0 0 0
Screening 12 24 36 48 Screening 12 24 36 48 trachomatis infections and syphilis.
(n = 557) (n = 482) (n = 467) (n = 437) (n = 424) (n = 557) (n = 482) (n = 464) (n = 434) (n = 418) The week 48 visit includes testing
Visit Week Visit Week performed at the optional follow-up
visit 4 weeks after week 48.

Early engagement, measured by clinic attendance and PrEP controlled studies. Three acute HIV infections were
adherence at week 4, was highly predictive of engagement at detected by HIV RNA at enrollment. Testing for HIV RNA at
the end of the study, highlighting the importance of early as- PrEP initiation would help to detect early infection and
sessment and support of adherence. Specifically, early moni- facilitate early initiation of antiretroviral therapy.
toring, such as testing for drug levels, could be useful in iden- We observed high STI positivity rates at baseline and dur-
tifying those who need additional support.45 Reductions in the ing follow-up, but the STI incidence was stable over time. The
cost and turnaround time of DBS testing would facilitate initial decline of rectal and pharyngeal STIs followed by an in-
implementation. crease may reflect clearance of prevalent infections at screen-
A substantial minority of participants reported 1 or more in- ing, regression to the mean, cohort and seasonal effects, and/or
terruptions in PrEP. Adverse effects were the most common rea- risk compensation. High STI rates were also observed among
son, suggesting the need for additional education and support MSM in the PROUD and IPERGAY studies.5,6 Although cur-
on the safety and tolerability of tenofovir-emtricitabine. Eleva- rent PrEP guidelines by the Centers for Disease Control and Pre-
tions of creatinine levels were uncommon, mostly uncon- vention recommend STI testing every 6 months,48 we recom-
firmed, and managed with regular monitoring. Although therapy mend quarterly screening for MSM taking PrEP, including
was discontinued 21 times owing to low self-perceived risk, most testing at extragenital sites.
of these participants reported recent sexual risk. Strategies to This study had several limitations. First, African Ameri-
improve risk perception, including online risk assessment tools46 can and transgender persons were underrepresented in the
and sexual diaries,47 may improve decisions about starting and sample, reflecting underrepresentation at the participating clin-
stopping PrEP. ics. This underrepresentation highlights the need for addi-
Despite a high incidence of STI acquisition and reported tional strategies to engage these populations and to deliver PrEP
risk behaviors, we observed a very low incidence of HIV in settings in which these individuals feel comfortable and safe
acquisition (0.43 infections per 100 person-years), with only receiving care. For example, integration of PrEP into trans-
2 incident infections. Both participants had low or unde- gender health care, including provision of cross-sex hor-
tectable TFV-DP levels, a pattern seen in the recent Pre- mone treatments, may increase uptake in that population.49
exposure Option for Reducing HIV in the UK (PROUD)5 and Second, although we conducted this study in 3 diverse US clin-
On Demand Antiretroviral Pre-exposure Prophylaxis for HIV ics, these results may not generalize to the broader MSM popu-
Infection in Men Who Have Sex With Men (IPERGAY) 6 lation in these cities, other parts of the United States, or inter-
PrEP trials. These studies, with similarly high reported risk national settings. Finally, although this project sought to assess
and STI prevalence and high HIV incidence in the placebo PrEP use in clinical settings where medication and monitor-
arms (8.9 and 6.8 per 100 person-years in the PROUD and ing were provided for free, cost and lack of insurance cover-
IPERGAY studies, respectively), demonstrated high levels of age may present significant barriers to PrEP access and adher-
PrEP efficacy (86%) and low numbers needed to treat (13 ence outside of a study, particularly in states with weak safety
and 18 in the PROUD and IPERGAY studies, respectively). nets.50 Strategies to increase affordability are critical to en-
The low HIV incidence observed in the Demo Project likely suring PrEP access to all individuals at risk for HIV. Cost-
reflects high overall adherence to PrEP and demonstrates effectiveness studies of different PrEP delivery models are also
that high levels of effectiveness can be achieved outside needed to inform PrEP implementation.

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 Preexposure Prophylaxis for HIV Infection Original Investigation Research

risk behaviors. These results provide support for expanding

Conclusions PrEP implementation in MSM in similar clinical settings and
highlight the urgent need to increase PrEP awareness and
The incidence of HIV acquisition was extremely low despite engagement and to develop effective adherence support
a high incidence of STIs in the study population. Adherence for highly affected African American and transgender
was higher among those participants with more reported populations.

ARTICLE INFORMATION Conflict of Interest Disclosures: Dr Rawlings Henry L. Boza, BA (outreach supervisor), Gregory
Accepted for Publication: July 19, 2015. reports employment by Gilead Sciences. Dr Tapia, MPH (outreach coordinator), Isabella
Anderson reports receiving study drug and contract Rosa-Cunha, MD (study clinician), Maria L. Alcaide,
Published Online: November 16, 2015. work from Gilead Sciences. Dr Philip reports MD (study clinician), Faith Doyle, FNP (study
doi:10.1001/jamainternmed.2015.4683. receiving research support from Cepheid, Inc, clinician), and Khemraj Hirani, PhD (study
Author Affiliations: San Francisco Department of SeraCare Life Sciences, Melinta Therapeutics, pharmacist), University of Miami Miller School of
Public Health, San Francisco, California (Liu, Cohen, Abbott Diagnostics, and Roche Diagnostics. Dr Medicine; and Justin Schmandt, MPH (research
Bacon, Matheson, Trainor, Blue, Philip, Elion reports serving on the speakers bureaus of manager), Tina Celenza, PA-C (study clinician),
Buchbinder); Department of Medicine, University Gilead Sciences, BMS, Janssen, Viv, and Merck; Anna Wimpelberg, BA (research
of California, San Francisco (Liu, Cohen, Bacon, serving on the advisory boards of Gilead Sciences, associate/counselor), Gwendolyn Ledford, BA
Liegler, Philip, Buchbinder); Department of Janssen, and Viv; and receiving research grants (research associate/counselor), J. J. Locquiao, BA
Epidemiology and Biostatistics, University of from Gilead Sciences, Merck, BMS, Viv, and (research associate/counselor), and Adwoa Addai,
California, San Francisco (Vittinghoff, Buchbinder); Janssen. Drs Liu, Grant, and Buchbinder have led PharmD (study pharmacist), Whitman Walker
Skaggs School of Pharmacy and Pharmaceutical trials in which the study drug was donated by Health. These study personnel were supported by
Sciences, University of Colorado, Aurora Gilead Sciences. No other disclosures were study funds. Cherlynn Mathias, RN, BSN (program
(Anderson); Department of Medicine, Miller School reported. officer), and David Burns, MD, MPH, NIH, Clinical
of Medicine, University of Miami, Miami, Florida Funding/Support: This study was supported by Prevention Research Branch, NIAID, assisted with
(Doblecki-Lewis, Kolber); Division of AIDS, National grant UM1AI069496 from the National Institute for procuring study funding through the NIH, for which
Institutes of Health, Bethesda, Maryland (Chege); Allergies and Infectious Diseases (NIAID); by grant they received no compensation. Lisa Metsch, PhD,
DF/Net Research, Inc, Seattle, Washington (Postle); R01MH095628 from the National Institute for Columbia University, and Sarit Golub, PhD, MPH,
Department of Health Behavior and Health Mental Health; by grant P30AI073961 from the Hunter College and the Graduate Center, City
Education, School of Public Health, University of National Institutes of Health (NIH) (Miami Center University of New York, provided guidance with the
Michigan, Ann Arbor (Amico); Gilead Sciences, for AIDS Research); and by grant P30AI027763 protocol design and instrument development, for
Foster City, California (Rawlings); Department of from the NIH (Gladstone Institute of Virology and which they received no compensation.
Public Health Sciences, Miller School of Medicine, Immunology–University of California, San Francisco,
University of Miami, Miami, Florida (Estrada, Center for AIDS Research). The study drug and REFERENCES
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